A growing body of evidence suggests that autism is a disorder of brain connectivity. Alterations in intra- and inter-hemispheric white matter volume/area and in clusters of structures whose volumes covary have been observed. Functional MRI studies have reported alterations in activation patterns within cortical and subcortical gray structures and reductions in functional connectivity within and between neural networks in autism. Our preliminary DTT studies indicate that subjects with high-functioning autism have abnormalities in a recently defined pathway interconnecting the amygdala and hippocampus with the mid-fusiform gyrus; that is, higher anisotropy, suggesting smaller fiber diameters and denser fiber packing, on the right as compared with the left, that was correlated with lower performanceon face processing tests. This study supports the capacity of DTT for identifying brain microstructure central to autism making links to the phenotype. We propose to study the anatomic connectivity and microstructural abnormalities of the brain in autism by using diffusion tensor magnetic resonance imaging (DT-MRI or DTI) and diffusion tensor tracking (DTT). We will measure microscopic structural changes in white matter pathways that interconnect specific brain regions and the associated gray matter regions in 40 individually-matched pairs of adults (age18-35 yrs)and 30 individually-matched pairs of children (age 6-11 yrs) with and without autism. We will correlate those results with behavioral measures related to these pathways. We will complete a related histopathological study of intracortical myelinated fibers that project into white matter and form association, projection, and commissural (corpus callosal) pathways. We will measure the volumes of gray and white matter structures to correlate with the DT-MRI and DTT findings. The results of this Project will provide a comprehensive understanding of brain microstructure and histopathology and its relation to structural connectivity as measured by DTI and functional connectivity in Projects II and III with whom subjects will be shared. This project will also provide critical insight into the structural outcome of the early disturbances in brain growth in autism. This Project will address Autism Research Matrix goals 6, 22, 23 and 34 on the neuropathology of autism and brain structure and function associated with autism. It also develops DDT methods for the study of pathways specific to autism.